Project Summary Age-related macular degeneration (AMD) is the leading cause of vision loss in the developed world affecting 11% of adults over the age of 85. In the United States alone, the disease currently afflicts 10 million individuals with health care costs in the billions of dollars. The 2005 discovery of a Y402H variant in complement factor H (CFH) as a risk factor for AMD was a major advance in AMD genetics, however the functional significance of CFH and Y402H in AMD and the pathogenic mechanisms that initiate the disease process remain poorly understood. This proposal will investigate a functional and structural CFH homolog in C. elegans, nematode complement factor H (nCFH). Although the prevailing hypothesis is that CFH mutations result in ectopic activation of the alternate complement pathway in the retina, preliminary studies indicate nCFH assembles on the ciliated dendritic tips of C. elegans mechanosensory neurons where it has a role in maintaining proximal cilia compartment structural integrity. Additional preliminary data indicate that cilia compartment structural integrity is compromised in CFH-/- mouse and human Y402H photoreceptors, indicating that this novel function for nCFH is conserved in its vertebrate CFH homologs. On the basis of this data, the PI proposes the radical hypothesis that CFH is an essential structural component of sensory neurons cilia in the vertebrate retina and that defects in sensory neuron cilia promote AMD pathogenesis in patients with CFH loss-of-function mutations. The aims of this proposal will extend these preliminary studies and will determine 1) the structural and functional consequences associated with nCFH partial and complete loss-of-function mutations and 2) identify cilia, cell surface, and extracellular components necessary for nCFH assembly and function. Together, the proposed work will provide substantial insight into non-canonical functions of CFH that are likely to contribute to a novel mechanism of AMD pathogenesis. !